Cachexia, also referred to as cachexy, is a systemic syndrome having major symptoms such as remarkable body weight loss, anemia, edema, anorexia, general prostration, malaise and the like in chronic diseases such as malignant tumor, tuberculosis, diabetes, blood diseases, endocrine disorders, infections, acquired immunodeficiency syndrome and the like (J. Parenteral and Enteral Nutrition, 12, 286-298 (1988) and Am. J. Med., 85, 289-291 (1988)).
Among those kinds of cachexia, a particular kind of cachexia caused by malignant tumor, that is, cancer cachexia is often observed, and cancer cachexia is said to account for about 20% of the deaths from malignant tumor (J. Natl. Cancer Inst., 89, 1763-1773 (1997)). In cancer cachexia, the progression of cachexia significantly weakens the physical strength of patients, and thus it does not allow the patients to be treated with antitumor agents, which are generally highly toxic, and it seriously undermines the treatment of malignant tumors. Furthermore, nutritional support to ameliorate the symptoms of cachexia can conversely lead to exacerbation of malignant tumor, reduced quality of life (QOL) of the patient and decreased lifetime. Moreover, in cases of cancer cachexia, administration of an antitumor agent may induce antitumor effects, but the administration, in most cases, rather causes side effects of the antitumor agents such as bone marrow toxicity and the like, and thus cachexia is not ameliorated (J. Clin. Oncol., 12, 213-225 (1994)).
Up to this point, as a substance having an ameliorating effect on cachexia, 1,2-diphenylpyrrole derivatives (JP 2000-095685 A), carboxylic acid amide derivatives (JP Hei 5-043466 A), parathyroid hormone-related peptide antibodies (WO 98/051329), ghrelin-like small molecule compounds (WO 05/097261), androgen receptor modulators (WO 02/066475) and the like are known. Even now, however, the pathogenesis of cachexia is unclear, and no agent is effective enough to be clinically used as a therapeutic agent for cachexia.
Meanwhile, a compound having a morphinan skeleton or a pharmacologically acceptable acid addition salt thereof has been disclosed to have an agonistic activity on the kappa opioid receptor, and the uses as an analgesic and a diuretic have been disclosed (WO 93/015081). Furthermore, the uses of the compound or the acid addition salt as an antitussive (WO 95/001178), a brain cell protecting agent (WO 95/003307), an antipruritic (WO 98.023290), a therapeutic agent for hyponatremia (WO 99/005146), an ORL-1 receptor antagonist (JP 2000-053572 A), a therapeutic agent for neuropathic pain (WO 01/014383), an antipruritic for cornea or conjunctiva (JP 2001-163784 A), a therapeutic agent for neuropsychiatric disorder (WO 02/078744), a therapeutic agent for drug dependence (WO 99/011289), a therapeutic agent for septicemia (WO 02/089845), a therapeutic agent for multiple sclerosis-associated pain (WO 06/095836), a therapeutic agent for schizophrenia (WO 09/001764), a therapeutic agent to improve skin conditions (WO 09/044883) and a therapeutic agent for dyskinesia (WO 08/133297) have been disclosed and, though published after the priority date of this application, the uses of the compound or the acid addition salt as a therapeutic agent for fibromyalgia (JP 2011-074018 A) and a therapeutic agent for biliary tract disease (WO 11/093441) have also been disclosed. However, the therapeutic or prophylactic effect thereof for cachexia has not been disclosed at all.
It could therefore be helpful to provide a therapeutic or prophylactic agent for cachexia which comprises as an effective ingredient a compound having a morphinan skeleton or a pharmacologically acceptable acid addition salt thereof and is capable of preventing or ameliorating the progression of symptoms of cachexia.